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Several studies have now demonstrated that bone marrow-derived cells can produce hepatocytes. Petersen et al. demonstrated the contribution of hematopoietic stem cells to oval cells, which are believed to be the resident stem cell of the liver (22). Donor contribution to host liver was shown in three ways:

1. Male donor marrow was infused into female recipients.

2. Cells obtained from dipeptidyl peptidase IV (DPP-IV)-positive male rats were transplanted into DPP-I-negative female rats.

3. Whole liver transplants were performed using Lewis rats expressing the L21-6 antigen as recipients and Brown-Norway rats not expressing this antigen as the allogeneic bone marrow transplant donors (23).

In bone marrow transplant models, unmanipulated bone marrow cells were transplanted into lethally irradiated hosts. Following engraftment, the animals were given 2-acetylaminofluorene, which blocks hepatocyte proliferation, and liver damage was induced using carbon tetrachloride. Two weeks following injury, donor contribution to the organ was determined. Between 0.1 and 0.15% of the hepatocytes were donor derived, and approx 0.1% of oval cells were donor derived (Fig. 2).

Theise et al. (24) showed that this phenomenon occurred in animals that had not incurred massive hepatic injury. A cohort of female mice received whole bone marrow cells from male mice following lethal irradiation. Mice were sacrificed at various times following transplant. In addition to looking at the effect of unseparated bone marrow, the investigators also looked at animals that had received sorted CD34posLinneg cells, a subset of bone marrow that includes hematopoietic stem cells. All animals had up to 2% donor-derived hepatocytes at 2 mo or longer posttransplant. Fluorescent in situ hybridization (FISH) analysis for the Y chromosome of the donor cells was utilized along with another probe to mRNA (messenger RNA) for albumin to ensure that the signal came from hepatocytes. This study demonstrated that the phenomenon of hepatic cell replacement was not completely dependent on tissue damage.

An additional study by Theise et al. (25) showed that this phenomenon is present following sex-mismatched human bone marrow transplant. Archived fixed tissue was obtained following two bone marrow transplants involving female recipients of bone marrow from male donors. In addition, tissue from patients who had undergone liver transplant for which the recipients were male and the donors were female were studied. Y chromosome-positive hepatocytes and cholangiocytes ranged from 4 to 43% and 4 to 38%, respec-

Fig. 2. Hepatic reconstitution of bone marrow derived cells. Brown Norway L21-negative liver was transplanted into a Lewis animal (L21 positive). At 75 d posttransplantation, liver damage was induced with carbon tetrachloride. The liver was harvested 15 d later and stained for L21. (Photomicrograph courtesy Bryon Petersen.) (See color plate 2 in the insert following p. 82.)

Fig. 2. Hepatic reconstitution of bone marrow derived cells. Brown Norway L21-negative liver was transplanted into a Lewis animal (L21 positive). At 75 d posttransplantation, liver damage was induced with carbon tetrachloride. The liver was harvested 15 d later and stained for L21. (Photomicrograph courtesy Bryon Petersen.) (See color plate 2 in the insert following p. 82.)

tively, with the highest levels seen in a patient with severe hepatic damage secondary to recurrent hepatitis C disease. This important study suggested that the phenomenon seen by Petersen and colleagues and Theise and coworkers in rodents also occurs in humans.

Lagasse et al. (26) published a study suggesting that hepatocytes derived from transplanted bone marrow cells are functional. In this study, a targeted mutation of fumarylacetoactetate hydrolase (FAH-/) in the mouse, an animal model of type I tyrosinemia, was utilized. These mice have an inborn error of metabolism that causes liver failure and necrosis. Provision of 2-(2-nitro-4-trifluoro-methylbenzyol)-1-3-cyclohexanedione (NTBC) protects the animals from liver failure and renal tubular damage. In one set of experiments, 1 million bone marrow cells were transplanted from male ROSA26/ 129SvJ mice, wild-type for FAH and transgenic for the lacZ gene, the Escherichia coli enzyme for P-Gal. The NTBC treatment was discontinued 3 wk after transplantation to give transplanted cells a selective advantage. After several months, 20 to 50% of the liver mass of FAH-/- mice transplanted in this manner contained lacZ staining cells.

In the second set of experiments (26), small numbers of donor cells that were highly enriched for hematopoietic stem cells based on expression of stem cell-specific antigens were injected along with 200,000 FAH-/- cells to promote survival from radiation conditioning. Animals that received 50 or more stem cells engrafted and had hepatic reconstitution, suggesting that the cells that repair the liver in this model are contained within the hematopoietic stem cell pool. In this study, they used the Y chromosome and P-Gal expression to establish donor identity. Bone marrow cells lacking expression of stem cell-specific antigens did not give rise to hema-tolymphoid engraftment or to hepatocytes, which demonstrates that the hematopoietic and hepatic activity is localized in the stem cell pool. Recently, however, two subsequent reports demonstrated that the rescue of hepatocyte function in this model system is a result of cell fusion rather than plasticity (26a,26b). This observation raises the intriguing possibility that primitive stem cells may be more fusogenic than other types of cells.

Krause et al. (27) performed a study to address the issue of the clonal origin of transdifferentiated tissue. Stem cells were first enriched from bone marrow based on negative selection for maturation antigens. These cells were then stained with a membrane-bound dye (PKH26) and transplanted into irradiated recipient mice. Two days later, PKH26-fluorescent cells were isolated from the bone marrow of transplanted animals, and single cells that had homed to the bone marrow were transplanted into secondary recipients. Of 30 recipient animals, 5 demonstrated engraftment of lymphoid and my-

eloid lineages long term. In addition, a high level of engraftment in epithelial tissues was observed. In this study, 0.5% of cholangiocytes were donor derived. Hepatocyte engraftment was not reported. Unexpectedly, a high level (20%) of alveolar epithelial cells were donor derived, as well as 3.4% of skin epithelium and lower levels of engraftment in the stomach, small and large bowel, and bronchi.

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